Development and Current State of Digital Therapeutics for Irritable Bowel Syndrome.

BACKGROUND & AIMS: Irritable bowel syndrome (IBS) is a common, debilitating disorder characterized by abdominal pain and disordered bowel habits. Current pharmacologic treatments often provide incomplete symptom relief and may be poorly tolerated. Furthermore, alleviation of gastrointestinal symptoms does not always translate into improved quality of life for IBS patients. Current treatment guidelines recommend brain-gut behavior therapy (BGBT) in conjunction with other IBS therapies, and, in randomized controlled trials, BGBT has been shown to improve symptoms, patient satisfaction, functioning, and quality of life. Access to BGBT is limited by lack of adequately trained gastrointestinal psychologists, patient time constraints, and cost. Furthermore, clinician knowledge that BGBT is specific, and different from psychotherapy approaches for common mental health disorders, may limit referrals even where available. This review provides an overview of the pathophysiology of IBS, disease burden, unmet therapeutic needs, evidence base of novel digital therapeutics for IBS, and guidance on the introduction and appropriateness of these interventions for patients. METHODS: We searched the literature for available published data relating to the use of novel digital therapeutics to provide cognitive behavioral therapy and gut-directed hypnotherapy in the treatment of irritable bowel syndrome. RESULTS: Clinical trial data support the development and utility of digital therapeutics designed to deliver self-guided cognitive behavioral therapy and hypnotherapy for the treatment of IBS. CONCLUSIONS: BGBTs are effective, guideline-recommended treatments for IBS. Digital therapeutic devices offer accessible, cost-effective treatment options for delivery of adjunctive BGBT for the treatment of IBS. The decision to recommend digital BGBTs should be guided by careful patient assessment that includes mental health screening and risk assessment.

Perceptions, Definitions, and Therapeutic Interventions for Occasional Constipation: A Rome Working Group Consensus Document.

BACKGROUND & AIMS: Functional constipation is the most common of the disorders of gut-brain interaction, affecting approximately 12% of the world population. Although classically considered a chronic condition, many individuals experience shorter yet repetitive bouts of constipation representing a different clinical entity. There has been increased interest in this latter disorder, which has recently been classified as occasional constipation. This Rome Foundation working group document reflects the consensus of an international team of specialists who summarized currently available research to provide a working definition of and treatment algorithm for occasional constipation. The recommendations herein are based on current evidence, accounting for gaps in the literature as well as international variance in definitions and health seeking behaviors for constipation. METHODS: The committee members reviewed the scientific literature, focusing specifically on occasional constipation, with the understanding that as a new entity, a paucity of data would be available. We used Rome IV research and clinical definitions to establish the framework for our definition of occasional constipation. Where possible, treatment recommendations were determined on the basis of the earliest extractable data from functional constipation studies, focusing on positive results within the first 2 weeks of treatment. We used the Delphi method to create consensus with 100% agreement between the authors. RESULTS: An evidence-based review of the literature resulted in the definition of occasional constipation as follows: "individuals who experience the presence of at least 1 functional constipation symptom, in the absence of alarm signs or symptoms, occurring at irregular and infrequent intervals, which is bothersome enough to induce a patient to seek medical management." Medical management whether seeking medical care or self-treatment was left to the individual's discretion, and we did not include time anchors because these thresholds require further investigation. Polyethylene glycol and stimulant laxatives are recommended as first-line interventions, whereas magnesium-containing compounds are suggested in individuals failing to respond to these therapies. There are insufficient data to make recommendations for using fiber or stool softeners. Prescription laxatives should be reserved for individuals with chronic constipation. CONCLUSIONS: Occasional constipation is a unique clinical entity characterized by infrequent but recurrent symptoms. Data are limited because consensus definitions have been lacking. Establishing a standardized definition and therapeutic recommendations provides a framework for future studies focusing on epidemiologic and symptoms-based outcomes. Further studies are needed to confirm and refine these recommendations.

Optimizing the Management Algorithm for Adults With Functional Constipation Failing a Fiber/Laxative Trial in General Gastroenterology: Cost-Effectiveness and Cost-Minimization Analysis.

INTRODUCTION: Anorectal function testing is traditionally relegated to subspecialty centers. Yet, it is an office-based procedure that appears capable of triaging care for the many patients with Rome IV functional constipation that fail empiric over-the-counter therapy in general gastroenterology, as an alternative to empirical prescription drugs. We aimed to evaluate cost-effectiveness of routine anorectal function testing in this specific population. METHODS: We performed a cost-effectiveness analysis from the patient perspective and a cost-minimization analysis from the insurer perspective to compare 3 strategies: (i) empiric prescription drugs followed by pelvic floor physical therapy (PFPT) for drug failure, (ii) empiric PFPT followed by prescription drugs for PFPT failure, or (iii) care directed by up-front anorectal function testing. Model inputs were derived from systematic reviews of prospective clinical trials, national cost data sets, and observational cohort studies of the impact of chronic constipation on health outcomes, healthcare costs, and work productivity. RESULTS: The most cost-effective strategy was upfront anorectal function testing to triage patients to appropriate therapy, in which the subset of patients without anal hypocontractility on anorectal manometry and with a balloon expulsion time of at least 6.5 seconds would be referred to PFPT. In sensitivity analysis, empiric PFPT was more cost effective than empiric prescription drugs except for situations in which the primary goal of treatment was to increase bowel movement frequency. If adopted, gastroenterologists would refer ∼17 patients per year to PFPT, supporting feasibility. DISCUSSION: Anorectal function testing seems to be an emergent technology to optimize cost-effective outcomes, overcoming testing costs by phenotyping care.

Abdominal Symptom Improvement During Clinical Trials of Tenapanor in Patients With Irritable Bowel Syndrome With Constipation: A Post Hoc Analysis.

INTRODUCTION: This post hoc analysis evaluated the efficacy of tenapanor on abdominal symptoms in patients with irritable bowel syndrome with constipation. Abdominal symptoms assessed included pain, discomfort, bloating, cramping, and fullness. METHODS: The abdominal symptom data were pooled from 3 randomized controlled trials (NCT01923428, T3MPO-1 [NCT02621892], and T3MPO-2 [NCT02686138]). Weekly scores were calculated for each abdominal symptom, and the Abdominal Score (AS) was derived as the average of weekly scores for abdominal pain, discomfort, and bloating. The overall change from baseline during the 12 weeks was assessed for each symptom weekly score and the AS. The AS 6/12-week and 9/12-week response rates (AS improvement of ≥2 points for ≥6/12- or ≥9/12-week) were also evaluated. The association of weekly AS response status (reduction of ≥30%) with weekly complete spontaneous bowel movement (CSBM) status (=0 and >0) was assessed. RESULTS: Among 1,372 patients (684 tenapanor [50 mg twice a day] and 688 placebo), the least squares mean change from baseline in AS was -2.66 for tenapanor vs -2.09 for placebo ( P < 0.0001). The 6/12-week AS response rate was 44.4% for tenapanor vs 32.4% for placebo ( P < 0.0001), and for 9/12-week AS, 30.6% for tenapanor vs 20.5% for placebo ( P < 0.0001). A significant association between weekly CSBM status and weekly AS response status was observed each week ( P < 0.0001), with a greater proportion achieving an AS reduction in patients with >0 CSBMs in a week. DISCUSSION: Tenapanor significantly reduced abdominal symptoms in patients with irritable bowel syndrome with constipation, particularly pain, discomfort, and bloating measured by AS, compared with placebo.

Plecanatide Improves Abdominal Bloating and Bowel Symptoms of Irritable Bowel Syndrome with Constipation.

BACKGROUND: Bloating is a bothersome symptom in irritable bowel syndrome with constipation (IBS-C). AIM: To evaluate plecanatide efficacy in patients with IBS-C stratified by bloating intensity. METHODS: Pooled phase 3 data (2 randomized, controlled IBS-C trials) from adults treated with plecanatide 3 mg or placebo for 12 weeks were analyzed. Patients were stratified post-hoc by baseline bloating severity (11-point scale: mild [≤ 5] and moderate-to-severe [> 5]). Assessments included change from baseline in bloating, abdominal pain, and complete spontaneous bowel movement (CSBM) frequency. Abdominal pain and bloating composite responders were defined as patients with ≥ 30% improvement from baseline in both bloating and abdominal pain at Week 12. RESULTS: At baseline, 1104/1436 patients with IBS-C (76.9%) reported moderate-to-severe bloating. In the moderate-to-severe bloating subgroup, plecanatide significantly reduced bloating severity versus placebo (least-squares mean change [LSMC]: - 1.7 vs - 1.3; P = 0.002), reduced abdominal pain (- 1.7 vs - 1.3; P = 0.006), and increased CSBM frequency (1.4 vs 0.8; P < 0.0001). In the mild bloating subgroup, significant improvements were observed with plecanatide versus placebo for abdominal pain (LSMC: - 1.3 vs - 1.0; P = 0.046) and CSBM frequency (2.0 vs 1.2; P = 0.003) but not bloating (- 0.9 vs - 0.8; P = 0.28). A significantly greater percentage of patients were abdominal pain and bloating composite responders with plecanatide versus placebo (moderate-to-severe bloating: 33.6% vs 26.8% [P = 0.02]; mild bloating: 38.4% vs 27.2% [P = 0.03]). CONCLUSION: Plecanatide treatment improved IBS-C abdominal and bowel symptoms, including in those who present with moderate-to-severe bloating.

Rare, Overlooked, or Underappreciated Causes of Recurrent Abdominal Pain: A Primer for Gastroenterologists.

Recurrent abdominal pain is a common reason for repeated visits to outpatient clinics and emergency departments, reflecting a substantial unmet need for timely and accurate diagnosis. A lack of awareness of some of the rarer causes of recurrent abdominal pain may impede diagnosis and delay effective management. This article identifies some of the key rare but diagnosable causes that are frequently missed by gastroenterologists and provides expert recommendations to support recognition, diagnosis, and management with the ultimate aim of improving patient outcomes.

Optimizing the Utility of Anorectal Manometry for Diagnosis and Therapy: A Roundtable Review and Recommendations.

BACKGROUND & AIMS: Anorectal manometry (ARM) is a comprehensive diagnostic tool for evaluating patients with constipation, fecal incontinence, or anorectal pain; however, it is not widely utilized for reasons that remain unclear. The aim of this roundtable discussion was to critically examine the current clinical practices of ARM and biofeedback therapy by physicians and surgeons in both academic and community settings. METHODS: Leaders in medical and surgical gastroenterology and physical therapy with interest in anorectal disorders were surveyed regarding practice patterns and utilization of these technologies. Subsequently, a roundtable was held to discuss survey results, explore current diagnostic and therapeutic challenges with these technologies, review the literature, and generate consensus-based recommendations. RESULTS: ARM identifies key pathophysiological abnormalities such as dyssynergic defecation, anal sphincter weakness, or rectal sensory dysfunction, and is a critical component of biofeedback therapy, an evidence-based treatment for patients with dyssynergic defecation and fecal incontinence. Additionally, ARM has the potential to enhance health-related quality of life and reduce healthcare costs. However, it has significant barriers that include a lack of education and training of healthcare providers regarding the utility and availability of ARM and biofeedback procedures, as well as challenges with condition-specific testing protocols and interpretation. Additional barriers include understanding when to perform, where to refer, and how to use these technologies, and confusion over billing practices. CONCLUSIONS: Overcoming these challenges with appropriate education, training, collaborative research, and evidence-based guidelines for ARM testing and biofeedback therapy could significantly enhance patient care of anorectal disorders.

Linaclotide Reduced Response Time for Irritable Bowel Syndrome With Constipation Symptoms: Analysis of 4 Randomized Controlled Trials.

INTRODUCTION: These post hoc analyses provide clinically relevant data concerning time to response for individual irritable bowel syndrome with constipation (IBS-C) symptoms after linaclotide use. METHODS: Time-to-response data were pooled from 4 randomized controlled trials. Response time for abdominal symptoms (pain, discomfort, and bloating) and complete spontaneous bowel movements (CSBMs) were analyzed using the Kaplan-Meier method; patients were categorized as early responders (≤4 weeks), late responders (>4-12 weeks), or nonresponders. RESULTS: Among 2,350 patients (1,172 placebo and 1,178 linaclotide 290 µg), >50% of patients with IBS-C who initiated linaclotide treatment experienced a decrease of ≥30% in abdominal pain, discomfort, or bloating within 3-4 weeks (median). The median time to achieving ≥3 CSBMs was 4 weeks. Although not all linaclotide-treated patients responded within 12 weeks, a late response occurred between 4 and 12 weeks in 1 in 6 patients for abdominal pain and in approximately 1 in 10 patients for CSBM frequency. Comparisons of early responders, late responders, and nonresponders for both response definitions indicated that women, Whites, and patients with less severe baseline abdominal symptoms were more likely to respond early. DISCUSSION: Although treatment responses with linaclotide occurred in >50% of patients with IBS-C within 4 weeks of treatment initiation, benefits for individual abdominal symptoms and/or CSBM frequency can still occur between 4 and 12 weeks. A lack of improvement in one symptom does not negate the possibility of response for others, highlighting the importance of discussing all symptoms with patients and not assuming treatment futility at 4 weeks.

Differential Diagnosis of Chronic Diarrhea: An Algorithm to Distinguish Irritable Bowel Syndrome With Diarrhea From Other Organic Gastrointestinal Diseases, With Special Focus on Exocrine Pancreatic Insufficiency.

Chronic diarrhea, defined as diarrhea persisting for more than 4 weeks, affects up to 5% of the population regardless of patient age, sex, race, or socioeconomic status. The impact on patient health and quality of life is substantial, and diagnosis and management of these patients have significant economic consequences for health care services. The differential diagnosis of chronic diarrhea is broad, with etiologies including infections, endocrinopathies, maldigestive/malabsorptive conditions, and disorders of gut-brain interaction. The considerable overlap of symptoms across this spectrum makes accurate diagnosis problematic and may lead to delays in diagnosis or misdiagnosis. In this narrative review, we consider the differential diagnosis of chronic diarrhea, focusing on irritable bowel syndrome with diarrhea and exocrine pancreatic insufficiency, two conditions that may present similarly but have very different underlying causes and require significantly different management strategies. We outline a 4-step diagnostic strategy and propose a straightforward algorithm to assist in efficiently differentiating irritable bowel syndrome from exocrine pancreatic insufficiency and other causes of chronic diarrhea. We anticipate that these aids will improve diagnostic accuracy, which ultimately should lead to improvements in patients' health-related quality of life and reduce the societal burden on health care services.

Re-evaluation of the Cardiovascular Safety Profile of Tegaserod: A Review of the Clinical Data.

BACKGROUND AND AIMS: Tegaserod is a 5-HT4 receptor agonist approved for irritable bowel syndrome with constipation in women <65 years of age without a history of cardiovascular ischemic events. Safety data are presented from 2 external adjudications from the 2018 Gastrointestinal Drugs Advisory Committee meeting supporting tegaserod's reintroduction after its voluntary 2007 withdrawal. Withdrawal was based on an internal adjudication using pooled placebo-controlled tegaserod data to identify potential cardiovascular ischemic signals. METHODS: An independent committee conducted an external adjudication to evaluate 24 possible cardiovascular ischemic events (tegaserod: n = 20; placebo: n = 4) identified internally. A second independent external adjudication further evaluated these events. RESULTS: A total of 18,645 patients were included (tegaserod: n = 11,614; placebo: n = 7031). The first adjudication identified 14 (0.075%) events (tegaserod: n = 13 [0.11%]; placebo: n = 1 [0.014%]). All patients had ≥1 cardiovascular risk factor, and 11 had ≥2. The second adjudication identified 390 events, 24 (0.13%) were classified as probable new or worsening events (tegaserod: 18 [0.16%]; placebo: 6 [0.09%]). For tegaserod, 7 (0.06%) were coronary or cerebrovascular ischemic events compared with 1 (0.01%) for placebo (odds ratio, 4.24; 95% confidence interval, 0.52-34.74; P = .273). All tegaserod patients reporting cardiovascular events had ≥1 risk, including cardiovascular disease, hyperlipidemia, ≥55 years of age, hypertension, diabetes, obesity, and smoking. Women <65 years of age without a history of cardiovascular ischemic events and ≤1 cardiovascular risk factor receiving tegaserod experienced no major adverse cardiovascular event(s). CONCLUSIONS: Two independent, external adjudications suggest that tegaserod is safe for women <65 years of age with irritable bowel syndrome with constipation, no history of cardiovascular ischemic events, and ≤1 cardiovascular risk factor.

Effective Communication Strategies and Tools for Improving Treatment Outcomes in Patients With Chronic Idiopathic Constipation and Irritable Bowel Syndrome With Constipation.

Patients with chronic idiopathic constipation and irritable bowel syndrome with constipation experience an array of gastrointestinal symptoms. Given the subjective nature of these disorders, patient self-reporting is critical to diagnosis and monitoring response to therapy. Unfortunately, many patients are reluctant to discuss bowel symptoms with their healthcare providers. Differences in sex, health literacy, and age can influence symptom reporting. Negative patient-physician relationships and dissatisfaction with care lead patients to seek alternative treatments, switch healthcare providers, or discontinue care. Thus, adopting a patient-centered communication style can help create a shared understanding of patients' symptoms, achieve accurate symptom reporting, expedite diagnosis, and facilitate appropriate treatment plans. Currently, there are multiple symptom and quality-of-life scales available to assist healthcare providers in this endeavor. These scales also allow for the monitoring of constipation-related symptoms and symptom severity. When using patient self-assessments to measure treatment responses, scale selection may depend on the number of symptoms being assessed, the duration and frequency of assessments, and patients' comprehension and language skills.

Mechanisms of Action of Current Pharmacologic Options for the Treatment of Chronic Idiopathic Constipation and Irritable Bowel Syndrome With Constipation.

Multiple therapeutic agents are currently available for the treatment of chronic idiopathic constipation and irritable bowel syndrome with constipation. A better understanding of the mechanism of action of each treatment provides important insights into expected responses and is key to optimizing treatment outcomes. Some constipation treatments, such as stimulant laxatives, may increase bowel movement frequency but are ineffective at relieving, and may even exacerbate, abdominal symptoms. On the contrary, prescription treatments, such as the guanylyl cyclase-C agonists, for example, may improve bowel symptoms and reduce visceral hypersensitivity. This review summarizes the mechanisms of action of commonly used over-the-counter and prescription therapies for chronic idiopathic constipation and irritable bowel syndrome with constipation, outlining how these mechanisms contribute to the efficacy and safety of each treatment option.

Real-World Treatment Strategies to Improve Outcomes in Patients With Chronic Idiopathic Constipation and Irritable Bowel Syndrome With Constipation.

Chronic idiopathic constipation and irritable bowel syndrome with constipation are complex, overlapping conditions. Although multiple guidelines have informed healthcare providers on appropriate treatment options for patients with chronic idiopathic constipation and irritable bowel syndrome with constipation, little direction is offered on treatment selection. First-line treatment options usually include fiber and over-the-counter osmotic laxatives; however, these are insufficient for many individuals. When these options fail, prescription secretagogues (plecanatide, linaclotide, lubiprostone, and tenapanor [pending commercial availability]), or serotonergic agents (prucalopride and tegaserod) are generally preferred. Individuals experiencing concurrent abdominal pain and/or bloating may experience greater overall improvements from prescription therapies because these agents have been proven to reduce concurrent abdominal and bowel symptoms. Should initial prescription treatments fail, retrying past treatment options (if not adequately trialed initially), combining agents from alternative classes, or use of adjunctive therapies may be considered. Given the broad spectrum of available agents, therapy should be tailored by mutual decision-making between the patient and practitioner. Overall, patients need to be actively monitored and managed to maximize clinical outcomes.

Baseline Predictors of Discontinuation of Prescription Drug Therapy for IBS-C: Cohort Analysis at an Integrated Healthcare System.

BACKGROUND: Effective prescription drug treatment of constipation-predominant irritable bowel syndrome (IBS-C) requires patients to remain on daily therapy, yet predictive factors to optimize treatment selection are unknown. AIMS: We assessed whether common comorbidities including chronic overlapping pain conditions (COPCs), mood disorders, or concurrent medications influence the risk of discontinuing IBS-C prescription drug therapy. METHODS: We included all IBS-C patients who initiated treatment with the secretagogues linaclotide or lubiprostone across the Michigan Medicine healthcare system between 2012 and 2016. A Cox proportional hazards model was constructed to model time-to-treatment discontinuation as a valid, quantifiable measure of IBS medication persistence using hazards ratios (HR) with 95% confidence intervals (CI). RESULTS: Our cohort included 225 patients on linaclotide and 492 on lubiprostone (mean age 48.3 years, 86.9% women, 46.6% with at least one COPC, 60.3% with at least one mood disorder) with an average follow-up of 2.1 years. Patients with at least one COPC (HR = 0.566; 95%CI = 0.371-0.863) and also women (HR = 0.535; 95%CI = 0.307-0.934) had a lower risk of discontinuing linaclotide, while COPCs predicted a trend toward increased discontinuation of lubiprostone (HR = 1.254; 95%CI = 0.997-1.576). Age, comorbid mood disorders, and baseline use of narcotics or benzodiazepines did not significantly mediate the risk of treatment discontinuation; our findings remained stable in univariate and multivariable analyses. CONCLUSIONS: COPCs and sex appear to influence the likelihood of discontinuation of two commonly prescribed secretagogues, while mood disorders, narcotics, and benzodiazepines may not. Routine assessment for comorbid COPCs prior to initiating therapy may optimize IBS-C treatment selection and outcomes in practice.

Efficacy and Safety of Over-the-Counter Therapies for Chronic Constipation: An Updated Systematic Review.

INTRODUCTION: Constipation is commonly treated with over-the-counter (OTC) products whose efficacy and safety remain unclear. We performed a systematic review of OTC therapies for chronic constipation and provide evidence-based recommendations. METHODS: We searched PubMed and Embase for randomized controlled trials of ≥4-week duration that evaluated OTC preparations between 2004 and 2020. Studies were scored using the US Preventive Services Task Force criteria (0-5 scale) including randomization, blinding, and withdrawals. The strengths of evidence were adjudicated within each therapeutic category, and recommendations were graded (A, B, C, D, and I) based on the level of evidence (level I, good; II, fair; or III, poor). RESULTS: Of 1,297 studies identified, 41 met the inclusion criteria. There was good evidence (grade A recommendation) for the use of the osmotic laxative polyethylene glycol (PEG) and the stimulant senna; moderate evidence (grade B) for psyllium, SupraFiber, magnesium salts, stimulants (bisacodyl and sodium picosulfate), fruit-based laxatives (kiwi, mango, prunes, and ficus), and yogurt with galacto-oligosaccharide/prunes/linseed oil; and insufficient evidence (grade I) for polydextrose, inulin, and fructo-oligosaccharide. Diarrhea, nausea, bloating, and abdominal pain were common adverse events, but no serious adverse events were reported. DISCUSSION: The spectrum of OTC products has increased and quality of evidence has improved, but methodological issues including variability in study design, primary outcome measures, trial duration, and small sample sizes remain. We found good evidence to recommend polyethylene glycol or senna as first-line laxatives and moderate evidence supporting fiber supplements, fruits, stimulant laxatives, and magnesium-based products. For others, further validation with more rigorously designed studies is warranted.

Antispasmodics for Chronic Abdominal Pain: Analysis of North American Treatment Options.

Chronic abdominal pain is a common gastrointestinal (GI) symptom that characterizes many functional GI disorders/disorders of gut-brain interaction, including irritable bowel syndrome, functional dyspepsia, and centrally mediated abdominal pain syndrome. The symptoms of abdominal pain in these highly prevalent disorders are often treated with antispasmodic agents. Antispasmodic treatment includes a broad range of therapeutic classes with different mechanisms of action, including anticholinergic/antimuscarinic agents (inhibition of GI smooth muscle contraction), calcium channel inhibitors (inhibition of calcium transport into GI smooth muscle), and direct smooth muscle relaxants (inhibition of sodium and calcium transport). The aim of this review article was to examine the efficacy and safety of antispasmodics available in North America (e.g., alverine, dicyclomine, hyoscine, hyoscyamine, mebeverine, otilonium, pinaverium, and trimebutine) for the treatment of chronic abdominal pain in patients with common disorders of gut-brain interaction. For the agents examined, comparisons of studies are limited by inconsistencies in treatment dosing and duration, patient profiles, and diagnostic criteria employed. Furthermore, variability in study end points limits comparisons. Risk of selection, performance, detection, attrition, and reporting bias also differed among studies, and in many cases, risks were considered "unclear." The antispasmodics evaluated in this review, which differ in geographic availability, were found to vary dramatically in efficacy and safety. Given these caveats, each agent should be considered on an individual basis, rather than prescribed based on information across the broad class of agents.

Tegaserod for Irritable Bowel Syndrome With Constipation in Women Younger Than 65 Years Without Cardiovascular Disease: Pooled Analyses of 4 Controlled Trials.

INTRODUCTION: Tegaserod was the first US Food and Drug Administration-approved drug for irritable bowel syndrome with constipation (IBS-C) in women and was recently reapproved for use. Recognizing that clinical trials were performed almost 20 years ago, we performed an integrated analysis on patient-reported outcomes relevant to current practice including previously unpublished data. METHODS: Data from 4 12-week, randomized, placebo-controlled trials evaluating tegaserod 6 mg b.i.d. in patients with IBS-C were pooled. We analyzed 2 groups: all women (overall population) and women younger than 65 years without a history of cardiovascular ischemic events (indicated population). The primary end point was subjective global assessment of IBS-C symptom relief. Responders rated themselves as "considerably" or "completely" relieved ≥50% of the time or at least "somewhat relieved" 100% of the time over the last 4 weeks. RESULTS: The overall and indicated populations included 2,939 (tegaserod [n = 1,478]; placebo [n = 1,461]) and 2,752 (tegaserod [n = 1,386]; placebo [n = 1,366]) participants, respectively. The pooled odds ratios (95% confidence interval) for clinical response during the last 4 weeks in the overall and indicated populations with tegaserod were 1.37 (1.18, 1.59; P < 0.001) and 1.38 (1.18, 1.61; P < 0.001). In the overall and indicated populations, clinical response rates for tegaserod during the last 4 weeks were 43.3% and 44.1% versus 35.9% and 36.5% with placebo (P < 0.001). Adverse events were similar between groups. No significant cardiovascular events related to tegaserod were observed in patients with ≤1 cardiac risk factor. DISCUSSION: Tegaserod 6 mg b.i.d. reduced IBS-C symptoms in overall and US Food and Drug Administration-indicated populations (women aged <65 years with no history of cardiovascular ischemic events).

ACG Clinical Guideline: Management of Irritable Bowel Syndrome.

Irritable bowel syndrome (IBS) is a highly prevalent, chronic disorder that significantly reduces patients' quality of life. Advances in diagnostic testing and in therapeutic options for patients with IBS led to the development of this first-ever American College of Gastroenterology clinical guideline for the management of IBS using Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Twenty-five clinically important questions were assessed after a comprehensive literature search; 9 questions focused on diagnostic testing; 16 questions focused on therapeutic options. Consensus was obtained using a modified Delphi approach, and based on GRADE methodology, we endorse the following: We suggest that a positive diagnostic strategy as compared to a diagnostic strategy of exclusion be used to improve time to initiating appropriate therapy. We suggest that serologic testing be performed to rule out celiac disease in patients with IBS and diarrhea symptoms. We suggest that fecal calprotectin be checked in patients with suspected IBS and diarrhea symptoms to rule out inflammatory bowel disease. We recommend a limited trial of a low fermentable oligosaccharides, disacchardies, monosaccharides, polyols (FODMAP) diet in patients with IBS to improve global symptoms. We recommend the use of chloride channel activators and guanylate cyclase activators to treat global IBS with constipation symptoms. We recommend the use of rifaximin to treat global IBS with diarrhea symptoms. We suggest that gut-directed psychotherapy be used to treat global IBS symptoms. Additional statements and information regarding diagnostic strategies, specific drugs, doses, and duration of therapy can be found in the guideline.

Evaluating the Impact of Cost on the Treatment Algorithm for Chronic Idiopathic Constipation: Cost-Effectiveness Analysis.

INTRODUCTION: Chronic idiopathic constipation (CIC) is a common and burdensome illness. We performed a cost-effectiveness analysis of the US Food and Drug Administration-approved CIC drugs to evaluate and quantify treatment preferences compared with usual care from insurer and patient perspectives. METHODS: We evaluated the subset of patients with CIC and documented failure of over-the-counter (OTC) osmotic or bulk-forming laxatives. A RAND/UCLA consensus panel of 8 neurogastroenterologists informed model design. Treatment outcomes and costs were defined using integrated analyses of registered clinical trials and the US Centers for Medicare and Medicaid Services-supported cost databases. Quality-adjusted life years (QALYs) were calculated using health utilities derived from clinical trials. A 12-week time horizon was used. RESULTS: With continued OTC laxatives, CIC-related costs were $569 from an insurer perspective compared with $3,154 from a patient perspective (considering lost wages and out-of-pocket expenses). CIC prescription drugs increased insurer costs by $618-$1,015 but decreased patient costs by $327-$1,117. Effectiveness of CIC drugs was similar (0.02 QALY gained/12 weeks or ∼7 healthy days gained/year). From an insurer perspective, prescription drugs (linaclotide, prucalopride, and plecanatide) seemed less cost-effective than continued OTC laxatives (incremental cost-effectiveness ratio >$150,000/QALY gained). From a patient perspective, the cost-effective algorithm started with plecanatide, followed by choosing between prucalopride and linaclotide starting at the 145-µg dose (favoring prucalopride among patients whose disease affects their work productivity). The patient perspective was driven by drug tolerability and treatment effects on quality of life. DISCUSSION: Addressing costs at a policy level has the potential to enable patients and clinicians to move from navigating barriers in treatment access toward truly optimizing treatment choice.

The influence of brain metastases on the central nervous system effects of methylnaltrexone: a post hoc analysis of 3 randomized, double-blind studies.

PURPOSE: Peripherally acting µ-opioid receptor antagonists such as methylnaltrexone (MNTX, Relistor®) are indicated for the treatment of opioid-induced constipation (OIC). The structural properties unique to MNTX restrict it from traversing the blood-brain barrier (BBB); however, the BBB may become more permeable in patients with brain metastases. We investigated whether the presence of brain metastases in cancer patients compromises the central effects of opioids among patients receiving MNTX for OIC. METHODS: This post hoc analysis of pooled data from 3 randomized, placebo-controlled trials included cancer patients with OIC who received MNTX or placebo. Endpoints included changes from baseline in pain scores, rescue-free laxation (RFL) within 4 or 24 h of the first dose, and treatment-emergent adverse events (TEAEs), including those potentially related to opioid withdrawal symptoms. RESULTS: Among 356 cancer patients in the pooled population, 47 (MNTX n = 27; placebo n = 20) had brain metastases and 309 (MNTX n = 172; placebo n = 137) did not have brain metastases. No significant differences in current pain, worst pain, or change in pain scores from baseline were observed between patients treated with MNTX or placebo. Among patients with brain metastases, a significantly greater proportion of patients who received MNTX versus placebo achieved an RFL within 4 h after the first dose (70.4% vs 15.0%, respectively, p = 0.0002). TEAEs were similar between treatment groups and were generally gastrointestinal in nature and not related to opioid withdrawal. CONCLUSION: Focal disruptions of the BBB caused by brain metastases did not appear to alter central nervous system penetrance of MNTX.